This program project application will serve to coordinate a multi-center approach to the design, synthesis, characterization, and testing of molecules that inhibit HIV-1 replication through inhibition of HIV-1 co- receptor activity. An outstanding international team of investigators has been selected for their potentially useful molecules through in vitro and in vivo testing. Project I will design and synthesize modified chemokine molecules that have promise as inhibitors of HIV co-receptor activity. Project II will test promising molecules for their activity against a variety of HIV clinical isolates and will characterize the emergence of resistance to these agents. Project III will examine the activity of promising compounds in the hu- PBL-SCID mouse. These studies will test the potential utility of targeting HIV co- receptors as a treatment strategy in HIV disease.